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<p>We investigated a novel <i>SLAMF7</i>-promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma, an incurable hematological malignancy. Ad[CE1A] infection, replication, and oncolysis were assessed in a panel of myeloma cell lines (n = 8) and ex vivo samples from myeloma patients (n = 17) and healthy donors (HDs) (n = 14). Ad[CE1A] efficiently infected, replicated, and induced oncolysis in myeloma cells, but not in control cell lines or HDs, demonstrating selective cytotoxicity. Mechanistic studies revealed Ad[CE1A]-induced cell death is caspase-independent, with a potential involvement of necroptosis. Ad[CE1A] also altered immunogenic cell death markers (calreticulin, CD47, extracellular ATP), enhanced antigen presentation via increased MHC class I and II receptor expression (HLA-ABC and HLA-DR), and stimulated bystander cytokine killing, indicating potential for direct and immune-mediated anti-myeloma responses. In vivo experiments with 5TGM1 syngeneic and U266 xenograft models showed Ad[CE1A] significantly reduced myeloma tumor burden compared to vehicle control. Combination therapy with anti-myeloma drugs, bortezomib, melphalan, panobinostat and pomalidomide, enhanced Ad[CE1A] efficacy, with melphalan upregulating <i>SLAMF7</i>, resulting in increased viral replication. In summary, these findings support Ad[CE1A] as a promising myeloma therapy.</p><p></p>

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An oncolytic adenovirus targeting SLAMF7 demonstrates anti-myeloma efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月17日

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  • Georgia Stewart,
  • Simon Tazzyman,
  • Yidan Sun,
  • Rebecca E. Andrews,
  • Jack Harrison,
  • Darren Lath,
  • Jenny Down,
  • Georgia Robinson,
  • Xue Wang,
  • Munitta Muthana,
  • Andrew. D. Chantry,
  • Michelle A. Lawson

摘要

We investigated a novel SLAMF7-promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma, an incurable hematological malignancy. Ad[CE1A] infection, replication, and oncolysis were assessed in a panel of myeloma cell lines (n = 8) and ex vivo samples from myeloma patients (n = 17) and healthy donors (HDs) (n = 14). Ad[CE1A] efficiently infected, replicated, and induced oncolysis in myeloma cells, but not in control cell lines or HDs, demonstrating selective cytotoxicity. Mechanistic studies revealed Ad[CE1A]-induced cell death is caspase-independent, with a potential involvement of necroptosis. Ad[CE1A] also altered immunogenic cell death markers (calreticulin, CD47, extracellular ATP), enhanced antigen presentation via increased MHC class I and II receptor expression (HLA-ABC and HLA-DR), and stimulated bystander cytokine killing, indicating potential for direct and immune-mediated anti-myeloma responses. In vivo experiments with 5TGM1 syngeneic and U266 xenograft models showed Ad[CE1A] significantly reduced myeloma tumor burden compared to vehicle control. Combination therapy with anti-myeloma drugs, bortezomib, melphalan, panobinostat and pomalidomide, enhanced Ad[CE1A] efficacy, with melphalan upregulating SLAMF7, resulting in increased viral replication. In summary, these findings support Ad[CE1A] as a promising myeloma therapy.